Effect on Gut Microbiome: Histamine-2 Receptor Antagonist vs Proton Pump Inhibitor
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
We aim to compare the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on the gut microbiota through longitudinal analysis.
DESIGN
Healthy volunteers were randomly assigned to receive either PPI (n=23) or H2RA (n=26) daily for seven consecutive days. We collected oral (saliva) and faecal samples before and after the intervention for metagenomic next-generation sequencing. We analysed intervention-induced alterations in the oral and gut microbiome including microbial abundance and growth rates, oral-to-gut transmissions, and compared differences between the PPI and H2RA groups.
RESULTS
Both interventions disrupted the gut microbiota, with PPIs demonstrating more pronounced effects. PPI usage led to a significantly higher extent of oral-to-gut transmission and promoted the growth of specific oral microbes in the gut. This led to a significant increase in both the number and total abundance of oral species present in the gut, including the identification of known disease-associated species like Fusobacterium nucleatum and Streptococcus anginosus. Overall, gut microbiome-based machine learning classifiers could accurately distinguish PPI from non-PPI users, achieving an area under the receiver operating characteristic curve (AUROC) of 0.924, in contrast to an AUROC of 0.509 for H2RA versus non-H2RA users.
CONCLUSION
Our study provides evidence that PPIs have a greater impact on the gut microbiome and oral-to-gut transmission than H2RAs, shedding light on the mechanism underlying the higher risk of certain diseases associated with prolonged PPI use.
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Additional Info
Disclosure statements are available on the authors' profiles:
Compared to histamine-2 receptor antagonist, proton pump inhibitor induces stronger oral-to-gut microbial transmission and gut microbiome alterations: a randomised controlled trial
Gut 2023 Nov 22;[EPub Ahead of Print], J Zhu, C Sun, M Li, G Hu, XM Zhao, WH ChenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The effect of long-term gastric acid suppression, particularly proton-pump inhibitors (PPIs), on human health has been the subject of intense debate. Previous studies have noted possible risks associated with PPI use, with the most consistent effect relating to infection, including Clostridioides difficile, other enteric infections, and pneumonia. PPIs have also been associated with changes in the gut microbiota, including loss of species diversity and increased abundance of enteric pathogens, leading to speculation that PPI-driven alterations in the microbiota provide a mechanistic explanation for their possible side effects. On the other hand, histamine-2 receptor antagonists (H2RAs) are less-potent acid suppressors, and there is a lack of evidence of similar disease associations for H2RAs. A direct comparison of microbiota changes during H2RA and PPI treatment has not previously been performed.
Zhu et al investigated the short-term effects of H2RAs and PPIs on the oral and gut microbiota. Consistent with previous studies, they found that a 1-week PPI treatment of healthy subjects causes a significant alteration in gut microbiota composition, with a strong signature of oral microbes transmitting to the stool. This effect was not observed in the H2RA-treatment group. While the majority of species transmitted from the oral microbiota were in the Streptococcus genus, several organisms associated with human disease were similarly identified. They conclude that oral-to-gut microbiota transmission during PPI therapy may enhance the risks associated with this drug class.
Several diseases have been described as correlating with PPI use in cohort-based studies, prospective studies, and meta-analyses including the aforementioned risk of infections, luminal GI diseases (eg, inflammatory bowel disease and colon cancer), and extra-intestinal diseases such as osteoporosis, dementia, and cancer. However, a large, multinational, randomised control trial only demonstrated an increase in non–C difficile–related enteric infections in the PPI-treatment group.1.
The results of Zhu et al verify the biological plausibility that PPIs increase the transmission of oral microbes into the gut microbiota. Indeed, most bacteria are unable to tolerate a typical gastric pH of approximately 2.0; therefore, PPI treatment likely enables the passage of acid-susceptible organisms into the intestine. In addition to enteric infections, other diseases have been postulated to occur as a result of oral-to-gut bacterial transmission, such as the IBD-associated Klebsiella pneumoniae clade Kp2.2,3 The authors note that the colon cancer–associated Fusobacterium nucleatum was identified in their cohort after PPI treatment, suggesting that long-term exposure could convey increased risk. Whether these and other disease-associated bacteria are causative in human illness and whether chronic PPI treatment induces their sustained colonization remains unknown.
The intersubject variability of the gut microbiota adds a layer of complexity, wherein common drugs may have uncommon effects on a minority of the treated population. This study highlights that, in the case of PPI treatment, the oral microbiome must also be taken into consideration.
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